8AOM

Complex of PD-L1 with VHH1

Summary for 8AOM

• Entry DOI: 10.2210/pdb8aom/pdb
• Descriptor: Programmed cell death 1 ligand 1, VHH6, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: single domain antibody, vhh, programmed cell death 1 ligand 1, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 38520.64

Authors

Kang-Pettinger, T.,Hall, G. (deposition date: 2022-08-08, release date: 2023-06-14, Last modification date: 2024-10-09)

Primary citation

Kang-Pettinger, T.,Walker, K.,Brown, R.,Cowan, R.,Wright, H.,Baravalle, R.,Waters, L.C.,Muskett, F.W.,Bowler, M.W.,Sawmynaden, K.,Coombs, P.J.,Carr, M.D.,Hall, G.
Identification, binding, and structural characterization of single domain anti-PD-L1 antibodies inhibitory of immune regulatory proteins PD-1 and CD80.
J.Biol.Chem., 299:102769-102769, 2023

PubMed Abstract: Programmed death-ligand 1 (PD-L1) is a key immune regulatory protein that interacts with programmed cell death protein 1 (PD-1), leading to T-cell suppression. Whilst this interaction is key in self-tolerance, cancer cells evade the immune system by overexpressing PD-L1. Inhibition of the PD-1/PD-L1 pathway with standard monoclonal antibodies has proven a highly effective cancer treatment; however, single domain antibodies (VHH) may offer numerous potential benefits. Here, we report the identification and characterization of a diverse panel of 16 novel VHHs specific to PD-L1. The panel of VHHs demonstrate affinities of 0.7 nM to 5.1 μM and were able to completely inhibit PD-1 binding to PD-L1. The binding site for each VHH on PD-L1 was determined using NMR chemical shift perturbation mapping and revealed a common binding surface encompassing the PD-1-binding site. Additionally, we solved crystal structures of two representative VHHs in complex with PD-L1, which revealed unique binding modes. Similar NMR experiments were used to identify the binding site of CD80 on PD-L1, which is another immune response regulatory element and interacts with PD-L1 localized on the same cell surface. CD80 and PD-1 were revealed to share a highly overlapping binding site on PD-L1, with the panel of VHHs identified expected to inhibit CD80 binding. Comparison of the CD80 and PD-1 binding sites on PD-L1 enabled the identification of a potential antibody binding region able to confer specificity for the inhibition of PD-1 binding only, which may offer therapeutic benefits to counteract cancer cell evasion of the immune system.

PubMed: 36470427
DOI: 10.1016/j.jbc.2022.102769

Experimental method

X-RAY DIFFRACTION (2.202 Å)